Metabotropni glutamatni receptor 3

Metabotropni glutamatni receptor 3
Metabotropni glutamatni receptor 3
	PDB prikaz baziran na 2e4u.
Dostupne strukture
	3SM9
Identifikatori
Simboli	GRM3; GLUR3; GPRC1C; MGLUR3; mGlu3
Vanjski ID	OMIM: 601115 MGI: 1351340 HomoloGene: 651 IUPHAR: mGlu3 GeneCards: GRM3 Gene
Ontologija gena
Molekularna funkcija	• aktivnost grupe II metabotropnog glutamatnog receptora; • aktivnost signalnog transducera; • receptorska aktivnost; • aktivnost G protein spregnutog receptora; • aktivnost regulatora kalcijumovog kanala; • aktivnost glutamatnog receptora;
Celularna komponenta	• ćelijska membrana; • integralno sa ćelijskom membranom; • postsinaptička gustina; • integralno sa membranom; • akson; • presinaptička membrana; • dendritska osnova; • postsinaptička membrana;
Biološki proces	• Signalni put G protein spregnutog receptora; • negativna regulacija aktivnosti adenilat ciklaze; • inhibicija adenilat ciklazne aktivnosti signalnim putem G protein spregnutog glutamatnog receptora; • sinaptička transmisija; • regulacija sinaptičke transmisije;
Pregled RNK izražavanja
	podaci
Ortolozi
Vrsta	Čovek
Entrez	2913
Ensembl	ENSG00000198822
UniProt	Q14832
RefSeq (mRNA)	NM_000840.2
RefSeq (protein)	NP_000831.2
Lokacija (UCSC)	Chr 7:; 86.27 - 86.49 Mb
PubMed pretraga	[1]

Metabotropni glutamatni receptor 3 je protein koji je kod ljudi kodiran GRM3 genom.^[1]^[2]

L-glutamat je jedan od glavnih ekscitatornih neurotransmitera centralnog nervnog sistema. On aktivira jonotropne i metabotropne glutamatne receptore. Glutamatergična neurotransmisija učestvuje u većini aspekata normalne moždane funkcije. Ona može da bude modifikovana mnogim neuropatološkim uslovima. Metabotropini glutamatni receptori su familija G protein spregnutih receptora, koji se dele u tri grupe na bazi homologije sekvenci, mehanizama prenosa signala, i farmakoloških svojstava. Grupa I obuhvata GRM1 i GRM5. Za njih je pokazano da aktiviraju fosfolipazu C. Grupa II obuhvata GRM2 i GRM3, dok su grupi III GRM4, GRM6, GRM7 i GRM8. Grupe II i III receptora su povezane sa inhibicijom kaskade cikličnog AMP-a, ali se razlikuju u selektivnost na agoniste.^[2]

Ligandi

Potpuno mGluR3 selektivni agensi nisu dostupni. Poznati su mešoviti mGluR2/3 (grupa II) ligandi sa selektivnošću u odnosu na druge mGluR podtipove. Neki od njih imaju nisku oralnu biodostupnost, ali postoji mogućnost njihove upotrebe u obliku proleka.^[3]

Agonisti

sa biciklo[3.1.0]heksanskom osnovom
- MGS-0028^[4]
- LY404040^[5]
- LY379268^[6]
- LY354740^[7]; njegov (+)-C4α-metil analog je GluR2 agonist / GluR3 antagonist^[8]
(R)-2-amino-4-(4-hidroksi[1,2,5]tiadiazol-3-il)buterna kiselina^[9]

Antagonist

CECXG - 38 puta je selektivniji za mGlu₃ u odnosu na mGlu₂
LY-341,495 i njegov 1-fluoro analog^[10]: potentni ortosterni antagonisti
MGS-0039^[11], HYDIA^[12] (oba sa biciklo[3.1.0]heksanskom osnovom)

Alosterni modulatori

MNI-137^[13]: inhibitor
jedinjenje 7p^[14]: nekompetitivni antagonist

Interakcije

Metabotropni glutamatni receptor 3 formira interakcije sa GRIP1,^[15] PICK1^[15] i PPM1A.^[16]

Reference

^ Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (1997). „Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q”. Genomics. 31 (2): 230—3. PMID 8824806. doi:10.1006/geno.1996.0036.
^ ^а ^б „Entrez Gene: GRM3 glutamate receptor, metabotropic 3”.
^ Rorick-Kehn LM; Perkins EJ; Knitowski KM; et al. (2006). „Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344”. J. Pharmacol. Exp. Ther. 316 (2): 905—13. PMID 16223873. doi:10.1124/jpet.105.091926.
^ Nakazato A; Kumagai T; Sakagami K; et al. (2000). „Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists”. J. Med. Chem. 43 (25): 4893—909. PMID 11123999. doi:10.1021/jm000346k.
^ Monn JA; Massey SM; Valli MJ; et al. (2007). „Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors”. J. Med. Chem. 50 (2): 233—40. PMID 17228865. doi:10.1021/jm060917u.
^ Monn JA; Valli MJ; Massey SM; et al. (1999). „Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors”. J. Med. Chem. 42 (6): 1027—40. PMID 10090786. doi:10.1021/jm980616n.
^ Monn JA; Valli MJ; Massey SM; et al. (1997). „Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties”. J. Med. Chem. 40 (4): 528—37. PMID 9046344. doi:10.1021/jm9606756.
^ Dominguez C; Prieto L; Valli MJ; et al. (2005). „Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist”. J. Med. Chem. 48 (10): 3605—12. PMID 15887967. doi:10.1021/jm040222y.
^ Clausen RP; Bräuner-Osborne H; Greenwood JR; et al. (2002). „Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid”. J. Med. Chem. 45 (19): 4240—5. PMID 12213064. doi:10.1021/jm020122x.
^ Sakagami K; Yasuhara A; Chaki S; et al. (2008). „Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist”. Bioorg. Med. Chem. 16 (8): 4359—66. PMID 18348906. doi:10.1016/j.bmc.2008.02.066.
^ a) Nakazato A; Sakagami K; Yasuhara A; et al. (2004). „Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists”. J. Med. Chem. 47 (18): 4570—87. PMID 15317467. doi:10.1021/jm0400294. ,
b) Yasuhara A; Nakamura M; Sakagami K; et al. (2006). „Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential”. Bioorg. Med. Chem. 14 (12): 4193—207. PMID 16487713. doi:10.1016/j.bmc.2006.01.060. ,
c) Yasuhara A, Sakagami K, Yoshikawa R, Chaki S, Nakamura M, Nakazato A (2006). „Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists”. Bioorg. Med. Chem. 14 (10): 3405—20. PMID 16431115. doi:10.1016/j.bmc.2005.12.061.
^ Woltering TJ; Adam G; Huguenin P; et al. (2008). „Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA”. ChemMedChem. 3 (2): 323—35. PMID 18058780. doi:10.1002/cmdc.200700226.
^ Hemstapat K; Da Costa H; Nong Y; et al. (2007). „A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors”. J. Pharmacol. Exp. Ther. 322 (1): 254—64. PMID 17416742. doi:10.1124/jpet.106.117093.
^ Woltering TJ; Wichmann J; Goetschi E; et al. (2008). „Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists”. Bioorg. Med. Chem. Lett. 18 (8): 2725—9. PMID 18374569. doi:10.1016/j.bmcl.2008.02.076.
^ ^а ^б Hirbec, Hélène; Perestenko Olga; et al. (2002). „The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs”. J. Biol. Chem. United States. 277 (18): 15221—4. ISSN 0021-9258. PMID 11891216. doi:10.1074/jbc.C200112200.
^ Flajolet, Marc; Rakhilin Sergey; et al. (2003). „Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3”. Proc. Natl. Acad. Sci. U.S.A. United States. 100 (26): 16006—11. ISSN 0027-8424. PMC 307683 . PMID 14663150. doi:10.1073/pnas.2136600100.

Literatura

Makoff A; Volpe F; Lelchuk R; et al. (1997). „Molecular characterization and localization of human metabotropic glutamate receptor type 3.”. Brain Res. Mol. Brain Res. 40 (1): 55—63. PMID 8840013. doi:10.1016/0169-328X(96)00037-X.
Emile L; Mercken L; Apiou F; et al. (1997). „Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3.”. Neuropharmacology. 35 (5): 523—30. PMID 8887960. doi:10.1016/0028-3908(96)84622-3.
Corti C; Sala CF; Yang F; et al. (2001). „Genomic organization of the human metabotropic glutamate receptor subtype 3.”. J. Neurogenet. 14 (4): 207—25, 271. PMID 11342382. doi:10.3109/01677060009084499.
Corti C, Xuereb JH, Corsi M, Ferraguti F (2001). „Identification and characterization of the promoter region of the GRM3 gene.”. Biochem. Biophys. Res. Commun. 286 (2): 381—7. PMID 11500049. doi:10.1006/bbrc.2001.5391.
Tomiyama M; Kimura T; Maeda T; et al. (2001). „Expression of metabotropic glutamate receptor mRNAs in the human spinal cord: implications for selective vulnerability of spinal motor neurons in amyotrophic lateral sclerosis.”. J. Neurol. Sci. 189 (1-2): 65—9. PMID 11535235. doi:10.1016/S0022-510X(01)00561-5.
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Martí SB, Cichon S, Propping P, Nöthen M (2002). „Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population.”. Am. J. Med. Genet. 114 (1): 46—50. PMID 11840505. doi:10.1002/ajmg.1624.
Kitano J; Kimura K; Yamazaki Y; et al. (2002). „Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins.”. J. Neurosci. 22 (4): 1280—9. PMID 11850456.
Hirbec H; Perestenko O; Nishimune A; et al. (2002). „The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs.”. J. Biol. Chem. 277 (18): 15221—4. PMID 11891216. doi:10.1074/jbc.C200112200.
Strausberg RL; Feingold EA; Grouse LH; et al. (2003). „Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.”. Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899—903. PMC 139241 . PMID 12477932. doi:10.1073/pnas.242603899.
Scherer SW; Cheung J; MacDonald JR; et al. (2003). „Human chromosome 7: DNA sequence and biology.”. Science. 300 (5620): 767—72. PMC 2882961 . PMID 12690205. doi:10.1126/science.1083423.
Fujii Y; Shibata H; Kikuta R; et al. (2004). „Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia.”. Psychiatr. Genet. 13 (2): 71—6. PMID 12782962. doi:10.1097/01.ypg.0000056682.82896.b0.
Aronica E; Gorter JA; IJlst-Keizers H; et al. (2003). „Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins.”. Eur. J. Neurosci. 17 (10): 2106—18. PMID 12786977. doi:10.1046/j.1460-9568.2003.02657.x.
Hillier LW; Fulton RS; Fulton LA; et al. (2003). „The DNA sequence of human chromosome 7.”. Nature. 424 (6945): 157—64. PMID 12853948. doi:10.1038/nature01782.
Flajolet M; Rakhilin S; Wang H; et al. (2004). „Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3.”. Proc. Natl. Acad. Sci. U.S.A. 100 (26): 16006—11. PMC 307683 . PMID 14663150. doi:10.1073/pnas.2136600100.
Yao Y, Koo JC, Wells JW, Hampson DR (2004). „Expression of a truncated secreted form of the mGluR3 subtype of metabotropic glutamate receptor.”. Biochem. Biophys. Res. Commun. 319 (2): 622—8. PMID 15178451. doi:10.1016/j.bbrc.2004.05.032.
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Vidi još

Metabotropni glutamatni receptor

Spoljašnje veze

„Metabotropic Glutamate Receptors: mGlu₃”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Архивирано из оригинала 08. 08. 2014. г.

[pmid8824806-1] Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (1997). „Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q”. Genomics. 31 (2): 230—3. PMID 8824806. doi:10.1006/geno.1996.0036.

[entrez-2] а ^б „Entrez Gene: GRM3 glutamate receptor, metabotropic 3”.

[3] Rorick-Kehn LM; Perkins EJ; Knitowski KM; et al. (2006). „Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344”. J. Pharmacol. Exp. Ther. 316 (2): 905—13. PMID 16223873. doi:10.1124/jpet.105.091926.

[4] Nakazato A; Kumagai T; Sakagami K; et al. (2000). „Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists”. J. Med. Chem. 43 (25): 4893—909. PMID 11123999. doi:10.1021/jm000346k.

[5] Monn JA; Massey SM; Valli MJ; et al. (2007). „Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors”. J. Med. Chem. 50 (2): 233—40. PMID 17228865. doi:10.1021/jm060917u.

[6] Monn JA; Valli MJ; Massey SM; et al. (1999). „Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors”. J. Med. Chem. 42 (6): 1027—40. PMID 10090786. doi:10.1021/jm980616n.

[7] Monn JA; Valli MJ; Massey SM; et al. (1997). „Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties”. J. Med. Chem. 40 (4): 528—37. PMID 9046344. doi:10.1021/jm9606756.

[8] Dominguez C; Prieto L; Valli MJ; et al. (2005). „Methyl substitution of 2-aminobicyclo[3.1.0]hexane 2,6-dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist”. J. Med. Chem. 48 (10): 3605—12. PMID 15887967. doi:10.1021/jm040222y.

[9] Clausen RP; Bräuner-Osborne H; Greenwood JR; et al. (2002). „Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid”. J. Med. Chem. 45 (19): 4240—5. PMID 12213064. doi:10.1021/jm020122x.

[10] Sakagami K; Yasuhara A; Chaki S; et al. (2008). „Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2-[1-amino-1-carboxy-2-(9H-xanthen-9-yl)-ethyl]-1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist”. Bioorg. Med. Chem. 16 (8): 4359—66. PMID 18348906. doi:10.1016/j.bmc.2008.02.066.

[11] ) Nakazato A; Sakagami K; Yasuhara A; et al. (2004). „Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists”. J. Med. Chem. 47 (18): 4570—87. PMID 15317467. doi:10.1021/jm0400294. ,
b) Yasuhara A; Nakamura M; Sakagami K; et al. (2006). „Prodrugs of 3-(3,4-dichlorobenzyloxy)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential”. Bioorg. Med. Chem. 14 (12): 4193—207. PMID 16487713. doi:10.1016/j.bmc.2006.01.060. ,
c) Yasuhara A, Sakagami K, Yoshikawa R, Chaki S, Nakamura M, Nakazato A (2006). „Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists”. Bioorg. Med. Chem. 14 (10): 3405—20. PMID 16431115. doi:10.1016/j.bmc.2005.12.061.

[12] Woltering TJ; Adam G; Huguenin P; et al. (2008). „Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid-HYDIA”. ChemMedChem. 3 (2): 323—35. PMID 18058780. doi:10.1002/cmdc.200700226.

[13] Hemstapat K; Da Costa H; Nong Y; et al. (2007). „A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors”. J. Pharmacol. Exp. Ther. 322 (1): 254—64. PMID 17416742. doi:10.1124/jpet.106.117093.

[14] Woltering TJ; Wichmann J; Goetschi E; et al. (2008). „Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists”. Bioorg. Med. Chem. Lett. 18 (8): 2725—9. PMID 18374569. doi:10.1016/j.bmcl.2008.02.076.

[pmid11891216-15] а ^б Hirbec, Hélène; Perestenko Olga; et al. (2002). „The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs”. J. Biol. Chem. United States. 277 (18): 15221—4. ISSN 0021-9258. PMID 11891216. doi:10.1074/jbc.C200112200.

[pmid14663150-16] Flajolet, Marc; Rakhilin Sergey; et al. (2003). „Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3”. Proc. Natl. Acad. Sci. U.S.A. United States. 100 (26): 16006—11. ISSN 0027-8424. PMC 307683 . PMID 14663150. doi:10.1073/pnas.2136600100.

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